HIV is mostly transmitted through mucosal surfaces. Systemic immunization by injections generally does not induce effective mucosal immune responses. Therefore, it is extremely important to develop an HIV vaccine to induce effective mucosal and systemic immune responses. Papillomaviruses naturally infect skin and mucosa (mucosa-tropic). Papillomavirus-like particles made of a structural protein, L1, are highly immunogenic. Foreign peptides can be inserted into L1's surface loops to form chimeric virus-like particles (CVLPs), which, upon immunization, can induce potent antibodies against the inserted peptides. CVLPs can also package DNA vaccine plasmids to form pseudoviruses. We hypothesize that papillomavirus-like particles can be used as a vector to deliver HIV-1 antigens (peptides and genes) to oral lymphoid tissues such as tonsils and induce effective mucosal (oral, intestinal, and vaginal) and systemic immune responses against HIV-1. We plan to insert peptides containing epitopes recognized by the known HIV-1 neutralizing antibodies (2F5 and 4E10) into bovine papillomavirus (BPV) L1 loops to form CVLPs. Further, we will make CVLPs presenting mutated epitopes from resistant HIV-1 clades and variants to broaden neutralizing spectrum. We will use the CVLPs to package a DNA plasmid encoding gp160 or Gag to make HIV-BPV pseudoviruses. We expect that the pseudoviruses will deliver HIV-1 gp41 neutralizing epitopes and genes encoding gp160 and Gag to oral and systemic lymphoid tissues, leading to mucosal and systemic gp41 and gp120- specific neutralizing antibodies and Gag and Envelop-specific cytotoxic T lymphocytes. We will also develop oral commensal bacteria (S. gordonii and L. acidophilus) that will produce these pseudoviruses inside the oral cavity (a live oral vaccine). We will determine if both forms of vaccines (the pseudoviruses and pseudoviruses in the commensal bacteria) are able to infect oral lymphoid tissues and induce mucosal and systemic HIV-1-specific immune responses in mice and rabbits. We will also determine if these vaccines can protect mice with human CD4 and CCR5 transgenes against HIV-1 challenge. Upon completion of the project, we will have selected the best vaccine candidate for oral mucosal delivery of HIV-1 antigens.Project Narrative: HIV infection causes AIDS, a serious global health problem. Currently there is no effective vaccine for HIV infection. This project is to develop a novel oral vaccine to treat and prevent HIV infection.